The specific aim of this proposal is to examine the role of glucocorticoids in the development of bile acid metabolism. Since the catabolism of cholesterol to bile acid is quantitatively the most important pathway by which cholesterol may be removed from the body, the proposal is designed to elucidate information on the role of glucocorticoids in the development of cholesterol homeostasis by focusing on the role of glucocorticoids in the development of bile acid biosynthesis. Male neonatal rats will be adrenalectomized at 1, 2, or 3 weeks of age. In order to prevent serious electrolyte imbalance, these animals will be maintained on 11 deoxycorticosterone (a potent mineralocorticoid) and the following parameters will be examined in order to monitor the development of bile acid metabolism: 1. Plasma cholesterol; 2. Plasma corticosterone; 3. Hepatic cholesterol 7Alpha-hydorxylase activity (the rate-limiting enzyme of bile acid biosynthesis); 4. Bile acid pool size; 5. Cholesterol and bile acid absorption; and 6. Fecal excretion of sholesterol and bile acids. The effect of timing of adrenalectomy during development on the effectiveness of glucocorticoid replacement therapy started after weaning will also be examined in a similar manner. Finally, since atherosclerotic lesions can be induced in rabbits in a relatively short time, the effect of glucocorticoid supplementation during the neonatal life of the rabbit on subsequent cholesterol and bile acid metabolism and response to a cholesterol 'challenge', will also be studied. Male neonatal rabbits will be injected with 100 Mug of dexamethasone 3 times/week until weaning (8 weeks old). After a subsequent 4 weeks on stock rabbit diet, they will be challenged with 0.5 percent cholesterol-containing diet for 3 months (24 weeks old) and their response will be quantitated in terms of the above-mentioned parameters in addition to atherosclerotic lesions in the aorta and coronary vessels. The long term objective of this proposal is to provide information that is vital for a more rational basis for interventions, started in early life, designed to improve the handling of cholesterol in adult life thereby reducing the risk for the development of atherosclerosis.